This invention is directed to a treatment of malignant tumors in vivo using the compound 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and related derivatives such as its esters.
Control of malignant tumors in man and animals still remains as an unrealized goal. Within the last several decades, understanding of malignancy has made significant progress; however, conquering of the malignant disease state has not been realized.
Conventional therapy of both humans and other valuable animal species inflicted with malignant tumors presently includes surgical excising of the tumor, local radiation therapy of the afflicted animal, and chemotheraphy by administration of a chemotheraputic agent to the animal. The death of a significant number of patients inflicted with malignant tumors is attributable not to the primary tumor but instead to metastasis of the primary tumor to secondary sites in the host. If a primary tumor is detected early, it normally can be eliminated by surgery, radiation or chemotheraphy or combinations of these. The metastatic colonies of these primary tumors, however, are exceedingly harder to detect and eliminate and the unsuccessful management of them remains a serious medical problem.
Tumors are normally classified either as benign or malignant. The malignant tumor is characterized from the benign by its ability to invade both surrounding tissue and to colonize distant sites via metastisis. Certain organs are more prone to metastasis than others. Included in this group would be the lung, the brain, the liver, the ovaries and the adrenal glands. It has further been suggested that both surgery and radiation of a primary tumor in certain instances actually promotes metastasis.
In view of the inability of current cancer therapy to successfully control the malignant tumor and its metastisis, it is evident that there exists a need for additional chemotheraputic agents.
In a paper entitled Synthesis and Antiviral Activity of Certain Thiazole C-Nucleosides, J. Med. Chem. 1977, Volume 20, No. 2, 256, I and my co-workers disclosed the synthesis of and certain preliminary in vitro antiviral activity of the compounds 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and 2-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)thiazole-4-carboxamide in an in vitro test system utilizing three viruses, type 1 herpes simplex virus, type 3 parainfluenza virus and type 3 rhinovirus. The in vitro activity of the compound 2-.beta.-D-ribofuranosylthiazole-4-carboxamide against these three viruses was only moderate. With the compound 2-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)thiazole-4-carboxamide, only moderate activity was seen with type 1 herpes simplex virus whereas with the type 3 parainfluenza and the type 13 rhinoviruses activity was negative. While certain marginal in vitro antiviral activity noted in the preceding was seen, quite to the contrary, in vivo antiviral testing for both 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and 2-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)thiazole-4-carboxamide, as judged by the number of test animal deaths, was negative. In the in vivo tests, the number of deaths for the test animals for both 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and 2-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)thiazole-4-carboxamide was equal to or exceeded the number of deaths of the placebo control animals indicating that both of the compounds 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and 2-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)thiazole-4-carboxamide demonstrated no useful in vivo antiviral activity.
With regard to the above noted in vitro antiviral testing of both 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and 2-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)thiazole-4-carboxamide, these compounds were tested against viruses for which the known antiviral compound RIBAVIRIN.RTM. is known to have positive antiviral acivity. In view of the preliminary marginal in vitro activity of 2-.beta.-D-ribofuranosylthiazole-4-carboxamide against these test viruses, it was expected that the spectrum of activity of 2-.beta.-D-ribofuranosylthiazole-4-carboxamide would be similar to the spectrum of activity of the compound RIBAVIRIN.RTM.. RIBAVIRIN.RTM. is known to be an active in vitro antiviral agent and in vivo antiviral and is further known to exhibit no significant antitumor activity. Additionally, certain derivatives of RIBAVIRIN.RTM. such as its 5' monophosphate are also known to be inactive as antitumor compounds. It was reasonable to expect, in comparing the preliminary in vitro antiviral activity of 2-D-ribofuranosylthiazole-4-carboxamide with that of RIBAVIRIN.RTM., that 2-.beta.-D-ribofuranosylthiazole-4-carboxamide would exhibit positive in vivo antiviral activity and negative antitumor activity similar to RIBAVIRIN.RTM.. Totally contrary to this, the compound 2 -.beta.-D-ribofuranosylthiazole-4-carboxamide possessed no useful in vivo antiviral activity and, quite unexpectedly, has demonstrated positive antitumor activity.
I have found that the compound 2-.beta.-D-ribofuranosylthiazole-4-carboxamide and its esters, including 2-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)thiazole-4-carboxamide and 2-(5-O-phosphoryl-.beta.-D-ribofuranosyl)thiazole-4-carboxamide exhibit antitumor activites of such significance as to be useful as antitumor agents in vivo.